The coordinated activities at centromeres of two key cell cycle kinases, Polo and Aurora B, are critical for ensuring that the two sister kinetochores of each chromosome are attached to microtubules from opposite spindle poles prior to chromosome segregation at anaphase. Initial attachments of chromosomes to the spindle involve random interactions between kinetochores and dynamic microtubules, and errors occur frequently during early stages of the process. The balance between microtubule binding and error correction (e.g., release of bound microtubules) requires the activities of Polo and Aurora B kinases, with Polo promoting stable attachments and Aurora B promoting detachment. This study concerns the coordination of the activities of these two kinases in vivo. INCENP, a key scaffolding subunit of the chromosomal passenger complex (CPC), which consists of Aurora B kinase, INCENP, Survivin, and Borealin/Dasra B, also interacts with Polo kinase in Drosophila cells. It was known that Aurora A/Bora activates Polo at centrosomes during late G2. However, the kinase that activates Polo on chromosomes for its critical functions at kinetochores was not known. This study shows that Aurora B kinase phosphorylates Polo on its activation loop at the centromere in early mitosis. This phosphorylation requires both INCENP and Aurora B activity (but not Aurora A activity) and is critical for Polo function at kinetochores. The results demonstrate clearly that Polo kinase is regulated differently at centrosomes and centromeres and suggest that INCENP acts as a platform for kinase crosstalk at the centromere. This crosstalk may enable Polo and Aurora B to achieve a balance wherein microtubule mis-attachments are corrected, but proper attachments are stabilized allowing proper chromosome segregation (Carmena, 2012).
Coordination of Polo and Aurora B activity at kinetochores is critical in early mitosis, as the two kinases play potentially antagonistic but complementary roles in regulating kinetochore-microtubule interactions. Aurora B is essential for the correction of aberrant attachments, and indeed, tethering Aurora B too close to kinetochores interferes with the formation of stable attachments. In contrast, Plk1 activity is required for initial stabilisation of microtubule attachments to kinetochores. It is suggested that interactions with INCENP may provide a mechanism to coordinate the activities of these two essential kinases during early mitosis (Carmena, 2012).
Recent studies suggest that Plk1 is activated at centrosomes when its T-loop (T210) is phosphorylated by Aurora A kinase-Bora, and that this promotes the G2/M transition upstream of Cdk1, although Polo activity is not required for mitotic entry. How Plk1 is activated at kinetochores remained an important unsolved question. The present results show that Aurora B and INCENP, which are concentrated at inner centromeres, function there to activate Polo by phosphorylating its T-loop (Carmena, 2012).
Plk1 recruitment to centromeres in late G2 has been variously proposed to be mediated by Bub1, INCENP, and BubR1. Another report implicated the self-primed interaction of Plk1 with PBIP1/CENP-U. This could potentially explain why Plk1 activity is reportedly required for its localisation to kinetochores in human cells (Carmena, 2012).
The current RNAi studies confirmed that Plk1 is partially dependent on the CPC for its centromeric localization in human cells. However, this appears not to be the case in Drosophila, where Polo is present at centromeres before NEB, at a time when INCENP is not yet concentrated at inner centromeres and before PoloT182ph, the active form of the kinase, is detected there. Indeed, no significant decrease was observed in kinetochore-associated Polo levels after INCENP RNAi in Drosophila cells (Carmena, 2012).
Although Polo targeting to kinetochores is independent of the CPC in Drosophila, its activation there does require the CPC with active Aurora B. The data suggest that INCENP binding to Polo facilitates its subsequent activation by Aurora B kinase. Indeed, INCENP and Polo interact physically in vitro and co-immunoprecipitate in mitotic cell extracts. Although most centromeric Polo kinase is concentrated in the outer kinetochore in prophase and prometaphase, active Polo (PoloT182ph) is also found in inner centromeres, where it overlaps with INCENP as confirmed by a proximity ligation assay (PLA)(Carmena, 2012).
A range of evidence presented in this study suggests that Aurora B is the upstream kinase responsible for Polo kinase activation at centromeres. Firstly, Aurora B phosphorylates Polo at Thr182 in vitro. Secondly, RNAi depletion of INCENP or Aurora B, but not Aurora A, reduces levels of active PoloT182ph at kinetochores. Thirdly, tissue culture cells and third larval instar neuroblasts treated with a specific inhibitor of Drosophila Aurora B kinase show decreased levels of PoloT182ph at kinetochores. In all of the preceding experiments, PoloT182ph levels are affected at kinetochores but not at centrosomes, where Polo is presumably activated by Aurora A. Importantly, this involvement of Aurora B in Polo activation at centromeres discovered in Drosophila is conserved for Plk1 in human cells (Carmena, 2012).
The current results suggest a model for interactions between Polo kinase and the CPC at centromeres (see Model for the interactions between the CPC and Polo kinase at the centromere/kinetochore). In Drosophila cells, Polo targets to centromeres before the CPC is recruited by Survivin binding to histone H3T3ph (Yamagishi, 2010: see Schematic depiction of the pathways that regulate CPC targeting to centromeres). At inner centromeres of chromosomes whose kinetochores are not under tension, Polo now binds to INCENP. This promotes Polo kinase activation, as Aurora B phosphorylates PoloT182. It is suggested that interactions with INCENP link the two complementary kinase activities, thereby potentially creating a microtubule attachment/detachment cycle at kinetochores. Such a cycle would not be possible without a balancing phosphatase activity, and PP2A-B56 has recently been shown to oppose both Aurora B and Plk1 activities at kinetochores to promote stable attachments (Carmena, 2012).
At metaphase, when chromosomes are bioriented and under tension, the CPC and Polo kinase exhibit only a partial overlap. A weakening of the INCENP/Polo PLA signals in metaphase suggests that Polo may be released from INCENP after its activation—possibly moving to the outer kinetochore. During metaphase, the CPC localizes in the inner centromere, stretching between sister kinetochores, whereas Polo and PoloT182ph concentrate mainly at the kinetochores. This separation may be necessary to allow Polo-mediated stabilisation of kinetochore-microtubule attachments. The coordinated activities of both kinases at kinetochores and their tension-mediated separation might facilitate a dynamic equilibrium between attached and unattached kinetochores, selectively stabilizing proper chromosome attachments (Carmena, 2012).
In summary, the results reveal that INCENP and Aurora B are responsible for Polo kinase activation at centromeres but not at centrosomes during mitosis. These experiments support the hypothesis that INCENP acts as a scaffold integrating the cross-talk between these two important mitotic kinases (Carmena, 2012).
borr is ubiquitously expressed in the early Drosophila embryo, suggesting maternal expression, although it appears to be restricted to the VNC and brain during later embryonic stages (Hanson, 2005).
In order to observe the subcellular localisation of Borr, Drosophila DmD8 cells were transfected with a construct encoding GFP-tagged full-length Borr. As expected, GFP-Borr is associated with chromatin during prometaphase (Eggert, 2004), and is subsequently concentrated at the central spindle midbody and at the cell cortex in the cleavage furrow during telophase and cytokinesis. This pattern will be referred to as 'localisation to the mitotic spindle'. Significantly, GFP-Borr colocalises with both endogenous Aurora B and Incenp, in agreement with the results by Eggert (Eggert, 2004), who also observed co-localisation of Borr and Aurora B throughout mitosis. These results are consistent with Borr being a CPC component, like its vertebrate counterparts (Hanson, 2005).
Cytokinesis involves temporally and spatially coordinated action of the cell cycle and cytoskeletal and membrane systems to achieve separation of daughter cells. To dissect cytokinesis mechanisms it would be useful to have a complete catalog of the proteins involved, and small molecule tools for specifically inhibiting them with tight temporal control. Finding active small molecules by cell-based screening entails the difficult step of identifying their targets. Parallel chemical genetic and genome-wide RNA interference screens were performed in Drosophila cells, identifying 50 small molecule inhibitors of cytokinesis and 214 genes important for cytokinesis, including a new protein in the Aurora B pathway (Borr). By comparing small molecule and RNAi phenotypes, a small molecule was identified that inhibits the Aurora B kinase pathway. The protein list provides a starting point for systematic dissection of cytokinesis, a direction that will be greatly facilitated by also having diverse small molecule inhibitors, which have been identified. Dissection of the Aurora B pathway, where a new gene and a specific small molecule inhibitor were found, should prove particularly beneficial. This study shows that parallel RNA interference and small molecule screening is a generally useful approach to identifying active small molecules and their target pathways (Eggert, 2004).
Aurora B, INCENP, and Survivin form the chromosomal passenger complex, which also includes CSC-1 in C. elegans and Borealin/Dasra B in humans. Aurora B kinase plays a number of roles during mitosis, including phosphorylating Histone H3 on Ser-10 and detecting errors in chromosome attachment in mitosis, and performs an essential, but poorly understood, function in cytokinesis. Chromosomal passenger proteins localize to the inner centromere during mitosis and move to the interzonal microtubules, the cleavage furrow, and eventually the midbody during cytokinesis. Because the sequences that targeted CG4454 and aurora B both had 21-bp overlaps with other genes in the dsRNA collection that was screened, dsRNA targeting different areas of these two genes were performed, and no change in phenotype was oberved. Since RNAi depletion of the new gene discovered in the screen, CG4454, resulted in the same phenotype as depletion of aurora B and INCENP, it was hypothesized that CG4454 could be a new member of the chromosomal passenger complex. Green fluorescent protein (GFP) fusion proteins were constructed to both C- and N-termini of CG4454. CG4454-GFP exhibited the signature localization of a passenger protein and co-localized with Aurora B throughout mitosis and cytokinesis, suggesting that it might be complexed to Aurora B. RNAi depletion of CG4454 or aurora B resulted in an absence of phosphorylated Histone H3 on mitotic chromosomes, further supporting the participation of CG4454 in the chromosomal passenger complex. Although CG4454 amino acid sequence reveals a remote similarity with Borealin/Dasra B (Gassmann, 2004), it is unclear at this point whether CG4454 is its Drosophila homolog. Unlike CG4454, RNAi depletion of Borealin does not significantly reduce Histone H3 phosphorylation (Gassmann, 2004). It might not be possible to confirm whether CG4454 and Borealin are related until structural information becomes available. However, to prevent further confusion in naming conventions, CG4454 has been named Borealin-related (Eggert, 2004).
E133 is a loss-of-function allele of CG4454, with a single base pair deletion at position 290 in the first exon of its coding region. The resulting frameshift introduces a stop codon immediately after this deletion into the predicted protein, truncating it after serine 98. Zygotic homozygosity for the borr mutation results in late embryonic lethality, but the mutant embryos lack overt morphological defects, probably owing to rescue by maternal gene product (Hanson, 2005).
Given its high expression levels in the embryonic nervous system, this tissue was scrutinised carefully, after staining embryos with Hoechst dye. Indeed, by stage 12, cells in the VNC and brain were detected with abnormally large nuclei. It is estimated that the volumes of the borr mutant VNC nuclei are on average ~3 times larger than those of wild-type VNC nuclei. This implies an increased DNA content (>2N) of the mutant cells, and suggests that borr loss affects the divisions of VNC cells. Similarly oversized nuclei were detected in other tissues (in addition to severe morphological defects such as failure of germ band retraction), after injection of borr dsRNA into wild-type embryos, which potentially also depletes maternal gene product. Thus, borr loss appears to affect many, if not all, dividing cells in the embryo (Hanson, 2005).
To monitor the mitotic events that are affected in the borr mutant embryos, these embryos were stained with an antibody against serine 10 phosphorylated histone H3 (P-H3), a histone modification specifically found in mitotic cells that has been ascribed to Aurora B kinase activity in several organisms, including Drosophila. Counting the mitotic cells per hemi-neuromere in wild-type and borr mutant embryos, it was found that these numbers are reduced significantly in the mutants, to ~50% of the wild type at stage 12, and to ~20% at stage 14. These estimates suggest that, in mutant embryos, the overall number of cells per hemi-neuromere is also lower than normal (although it is technically difficult to obtain accurate counts of total cell numbers). Nevertheless, these counts suggest that the fraction of mitotic cells (i.e., the mitotic index) in the VNC of borr mutant embryos may be reduced compared with the wild type (Hanson, 2005).
To see whether the borr mutation affects a specific mitotic stage, each P-H3-positive cell was classified as one of four different mitotic stages (based on the shapes of their chromatin masses), and the frequencies of these stages were determined as a percentage of the total of mitotic cells. This revealed that the percentages of prophase and prometaphase cells were higher in borr mutants compared with the wild type, whereas anaphases and telophases were underrepresented in the mutants. This profile shift of the mitotic stages appears to be progressive during embryonic development, and becomes more pronounced by stage 14 when telophases have become exceedingly rare, maybe as a result of cumulative defects during consecutive abnormal cell divisions. This profile shift suggests that borr loss causes a severe attenuation, or block, prior to metaphase (Hanson, 2005).
Two further features were noticeable in the P-H3 staining patterns of the borr mutant VNC cells. (1) Many of the rare anaphases detected at stage 12 appeared abnormal, showing evidence of uneven segregation of chromatin. (2) The P-H3 staining intensity was reduced markedly, which is particularly noticeable during metaphase, but also during telophase when P-H3 staining normally fades away. These observations are consistent with the profile shift of the mitotic stages in borr mutant embryos, and they underscore the notion that the first major defect during the mutant cell cycle occurs prior to metaphase. A similar prometaphase block has been reported for human Borealin (Gassmann, 2004) and for other CPC components (Adams, 2001; Giet, 2001) in Drosophila cells (Hanson, 2005).
To further study the function of borr during mitosis, dsRNA interference was used in Drosophila Kc167 tissue culture cells. Indeed, 72 hours after addition of borr-specific dsRNA, Kc167 cells displayed a range of mitotic defects when compared with their controls. Most notably, highly abnormal multipolar spindles were observed in mitotic cells, and interphase cells often showed single large nuclei -- reminiscent of the VNC nuclei in borr mutant embryos -- or became multi-nucleate. Some of these cells appear to have up to eight distinct nuclei, in addition to DNA fragments strewn around the cytoplasm. Similar phenotypes were observed in HeLa cells after RNAi-mediated depletion of Borealin, and also after RNAi-mediated depletion of CPC components in Drosophila cells (Adams, 2001; Eggert, 2004; Gassmann, 2004; Giet, 2001; Sampath, 2004). They support the notion that Borr is a functional ortholog of human Borealin. Furthermore, the multi-nucleate cells and the multipolar spindles suggest that Borr is required for faithful segregation of chromosomes during mitosis, and that its loss can cause polyploidy and/or aneuploidy (for simplicity, this will be referred to as 'polyploidy') (Hanson, 2005).
One crucial role of the CPC during mitosis is to mediate the H3 phosphorylation of serine 10 (P-H3) by Aurora B, as has been demonstrated in budding yeast, C. elegans and Drosophila (Adams, 2001; Giet, 2001; Hsu, 2000). The numbers of P-H3-positive (dividing) cells are reduced in the VNC of borr mutant embryos. Furthermore, the P-H3 levels of individual borr mitotic nuclei are typically reduced compared with those of wild-type nuclei. Often, they exhibit blotchy P-H3 staining rather than the more 'structured' staining outlining condensed chromosomes as observed in the wild type. A similar loss of P-H3 staining has also been observed in borr RNAi-depleted Kc167 cells (Eggert, 2004). This reduction of the P-H3 levels in borr mutant cells is consistent with a loss of Aurora B kinase activity and, thus, with a disruption of CPC function (Hanson, 2005).
Despite the strong reduction of the P-H3 levels in mitotic VNC cells of borr mutant embryos, these cells display only a slight undercondensation of their chromatin, although the degree of undercondensation is somewhat variable from cell to cell. These results suggest that borr may not be essential for chromatin condensation (Hanson, 2005).
To examine the effects of borr loss on actively dividing epithelial cells, FRT-FLP-mediated recombination was used to generate borr mutant clones in imaginal discs whose cells undergo cell divisions throughout larval development. If borr mutant clones are induced during early larval stages and examined in fully grown larval discs, these clones are rare and are much smaller than the corresponding wild-type twin spots, suggesting that a large fraction of the mutant cells die. Hoechst staining revealed that many of the surviving borr mutant cells are large, with giant but well-formed nuclei that appear healthy, and well integrated into the epithelial tissue (Hanson, 2005).
Imaginal discs bearing borr mutant clones were stained with antibodies against Incenp and Aurora B, to assess the effect of borr loss on these CPC components during mitosis. Wild-type cells in metaphase show characteristic well-ordered mitotic spindles, with distinct staining of Aurora B and Incenp at specific sites along condensed chromatin. By contrast, borr mutant cells invariably show abnormal mitotic spindles, including multipolar ones. Most of these mutant spindles do not show any chromatin-associated Incenp or Aurora B staining, although occasionally patches of Incenp staining can still be observed, but they do not seem to be associated with any of the spindle components. These staining patterns suggest that these CPC components fail to localise properly to mitotic spindles in the absence of borr (and their levels may also be reduced, though the low frequency of surviving borr mutant cells does not allow assessment of this quantitatively). Therefore, as in mammalian cells, the correct localisation of Incenp and Aurora B to mitotic spindles of dividing imaginal disc cells depends on Borr. This is further evidence that Borr is a CPC protein, and that it interacts functionally with other known CPC components (Hanson, 2005).
Early-induced borr mutant clones are rare, and are much smaller than their twin spots. Indeed, many twin spots do not appear to have mutant cells associated with them, indicating that the mutant cells have all died. The frequency of surviving borr mutant clones is increased if they are induced in a Minute background, which provides the mutant cells with a proliferative advantage. They can thus occupy a significant fraction of imaginal disc territories in third instar larvae. All discs are equally affected, and they tend to be smaller than wild-type discs at an equivalent stage. Larvae with these clones do not survive pupariation (Hanson, 2005).
Closer examination of the borr mutant cells revealed essentially two distinct phenotypes: large cells with giant well-formed nuclei, and cells that appear to be undergoing apoptosis. The clearest examples of the latter show compacted almost perfectly spherical nuclei that are found at the basal-most level of the disc epithelium, well separated from the healthy nuclei of the wing pouch. borr mutant cells were observed that may be at an earlier step in the apoptotic process: their nuclei are less compacted, and they are just beginning to drop basally within the epithelium. Antibody staining against active caspase 3 confirmed that the borr mutant cells with compacted DNA are indeed undergoing apoptosis, in contrast to the borr mutant cells that are well-integrated into the epithelium and display only background levels of active caspase 3 staining. Cells with low caspase staining can also be observed: these show apparently fragmented but not yet compacted DNA, and may thus represent an intermediate stage (Hanson, 2005).
These results, together with observations in Borr-depleted embryos and tissue culture cells, suggest that borr mutant cells can undergo several consecutive abnormal mitoses, which results in large polyploid cells that eventually undergo apoptosis. Apoptotic cells appear to be cleared by basal extrusion from the epithelium (Hanson, 2005).
To assess the consequences of Borr loss on the development of the imaginal discs, borr mutant clones were induced in first or early second instar larvae, and the resulting adult flies were examined. The most common defects in these flies are abnormal legs and rough eyes. In addition, they often show other striking defects in tissue architecture, e.g. large wing nicks. In all these cases, a twin spot is apparent, but no mutant tissue is detectable. This indicates that, by the adult stage, each of these early-induced borr mutant cells has undergone apoptosis. The nature and extent of the adult defects also suggests that they may be due partly to non-autonomous effects of the borr mutant clones on their neighbouring wild-type tissue (Hanson, 2005).
To gain more direct evidence for these putative non-autonomous effects, the expression of Wingless (Wg) was examined in wing discs bearing borr mutant clones: Wg is a secreted morphogen that is expressed in a thin stripe along the developing margin of the wild-type disc and controls its formation. As expected from the adult phenotypes, Wg expression is perturbed in various ways by borr mutant clones. Some of the surviving giant borr mutant cells within the Wg-expressing territory cause a significant lateral expansion of Wg staining by virtue of their sheer size. Other cases of expanded Wg staining are not detectably associated with mutant cells, and thus appear to be cell non-autonomous consequences of borr loss (Hanson, 2005).
Clear non-autonomous effects of borr mutant cells were observed if the expression of cut and senseless, two of the ultimate target genes responding to the Wg morphogen in the marginal region, were examined. For example, a single surviving giant borr mutant cell expressing high levels of Cut can cause suppression of Cut and Senseless expression in neighbouring wild-type cells. A similarly striking example is the introduction of a V shape into the patterns of Cut and Senseless expression caused by a borr mutant clone. The presence of a large twin spot associated with this abnormality indicates that the causative borr mutant clone arose early when the disc contained only a small number of cells. Again, the borr mutant cells have disappeared in this case, most likely through apoptosis. The kink introduced into the expression domains of both proteins appears to coincide with a rearrangement of cells in this region. Indeed, it appears that a single giant borr mutant cell, in the process of basal displacement, might drag along normal epithelial cells. Thus, apoptosis and basal extrusion of a giant cell may exert sufficient disruption of the epithelium to induce compensatory cell rearrangements aimed at repairing epithelial integrity, which in the event compromise patterning (Hanson, 2005).
If borr mutant clones are induced late (from the early third larval instar onwards), the resulting flies are viable and display no gross patterning defects. Indeed, analysis of marked clones and twin spots in adult wings suggests that all borr mutant clones are fully viable, given that they occupy roughly the same amount of territory as their twin spots. This is somewhat unexpected in the light of results with earlier-induced clones whose survival is severely compromised owing to abnormal mitoses. Indeed, the size of the late-induced borr mutant clone indicates that the mutant cells have survived three or four consecutive (abnormal) mitoses without entering the apoptotic pathway (Hanson, 2005).
Closer examination of the flies bearing late-induced borr mutant clones revealed that their wing blades contain clusters of hairs (trichomes) surrounded by large clearings, rather than the usual regularly spaced single hairs. The number of hairs per cluster varies, with the largest cluster observed consisting of 12 hairs. All these hair clusters are produced by borr mutant cells (as judged by their trichome marker), so this phenotype is strictly cell-autonomous. The borr mutant clones do not significantly affect the planar polarity in the wing blade; mutant and surrounding wild-type hairs appear normally oriented (Hanson, 2005).
Examination of borr mutant clones in pupal wing discs supports the notion that all late-induced borr mutant clones occupy roughly the same amount of territory as their twin spots, confirming that the mutant cells are fully viable at this stage. In support of this, no nuclei were observed with compacted DNA (that would indicate imminent apoptosis). As in the larval discs, the surviving borr mutant cells in the pupal discs are much larger than their neighbours, often with giant nuclei, indicating a high degree of ploidy. These giant borr mutant cells appear healthy and are well integrated within the epithelial tissue. Their large size provides an explanation for the observed adult phenotype, and are consistent with a single borr mutant cell producing multiple hairs: other conditions that produce large cells for example, cdc2, UltA or UltB mutant clones, or wounding result in similar cell-autonomous clusters of trichomes, albeit in some cases with fewer hairs per cluster (Hanson, 2005).
Abnormal giant bristles were observed in the wing margins of flies bearing late-induced borr mutant clones; these giant bristles invariably lack sockets. Since it was not possible to determine whether these abnormal bristles are derived from mutant cells (owing to the weak phenotype of their bristle marker), incipient bristles were visualized in the pupal wing by ß-tubulin antibody staining. This revealed large borr mutant trichogen cells (identifiable by their lack of GFP) that generate bristles twice the normal size. In addition, unlike wild-type bristles, these giant bristles do not exhibit any ß-tubulin accumulation at their bases, confirming that the developing socket is absent around the borr mutant bristles (Hanson, 2005).
Bristles are part of sensory organs, which are composed of four cells -- the trichogen (bristle-producing cell), tormogen (socket-producing cell), neuron and thecogen (sheath cell); these are the progeny of a single sensory organ precursor cell produced by consecutive invariant lineage divisions. Evidently, loss of borr compromises the lineage-generating divisions, and the single polyploid mutant cell seems to develop invariably as a trichogen at the expense of the tormogen and, possibly, of the other two sensory organ cells (Hanson, 2005).
Reference names in red indicate recommended papers.
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Carmena, M. and Earnshaw, W. C. (2003). The cellular geography of aurora kinases. Nat. Rev. Mol. Cell. Biol. 4: 842-854. 14625535
Carmena, M., Pinson, X., Platani, M., Salloum, Z., Xu, Z., Clark, A., Macisaac, F., Ogawa, H., Eggert, U., Glover, D. M., Archambault, V. and Earnshaw, W. C. (2012). The chromosomal passenger complex activates Polo kinase at centromeres. PLoS Biol 10: e1001250. PubMed ID: 22291575
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Jeyaprakash, A. A., Klein, U. R., Lindner, D., Ebert, J., Nigg, E. A. and Conti, E. (2007). Structure of a Survivin-Borealin-INCENP core complex reveals how chromosomal passengers travel together. Cell 131(2): 271-85. Medline abstract: 17956729
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Romano, A., Guse, A., Krascenicova, I., Schnabel, H., Schnabel, R. and Glotzer, M. (2003). CSC-1: a subunit of the Aurora B kinase complex that binds to the survivin-like protein BIR-1 and the incenp-like protein ICP-1. J. Cell Biol. 161: 229-236. 12707312
Sampath, S. C., Ohi, R., Leismann, O., Salic, A., Pozniakovski, A. and Funabiki, H. (2004). The chromosomal passenger complex is required for chromatin-induced microtubule stabilization and spindle assembly. Cell 118: 187-202. 15260989
Vader, G., Kauw, J. J., Medema, R. H. and Lens, S. M. (2006). Survivin mediates targeting of the chromosomal passenger complex to the centromere and midbody. EMBO Rep. 7(1): 85-92. 16239925
Yamagishi, Y., Honda, T., Tanno, Y. and Watanabe, Y. (2010). Two histone marks establish the inner centromere and chromosome bi-orientation. Science 330: 239-243. PubMed ID: 20929775
Yang, D., Welm, A. and Bishop, J. M. (2004). Cell division and cell survival in the absence of survivin. Proc. Natl. Acad. Sci. 101: 15100-15105. 15477601
Yu, S. Y., Yoo, S. J., Yang, L., Zapata, C., Srinivasan, A., Hay, B. A. and Baker, N. E. (2002). A pathway of signals regulating effector and initiator caspases in the developing Drosophila eye. Development 129: 3269-3278. 12070100
date revised: 25 May 2013
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